The aim of the present proposal is to investigate genetic and epigenetic (i.e., intrinsic and extrinsic) mechanisms controlling axonal growth, during development, of one part of the central MA system: the locus coeruleus (LC) projection to the hippocampus. This study can now be performed at the genetic level by utilizing the neurological mutant mouse tottering (tg/tg) as a model system. The single locus mutation results in expressed focal motor and spike-wave absence seizures, in the absence of any obvious neuropathology. Recent analysis of the catecholamine (CA) system in this mouse demonstrated an abnormal, 2-3 fold increase of its axonal projection by a normal numbere of LC neurons to all LC target areas (1). No other CA systems are affected. It will be determined, using this genetic lesion, how the abnormal exuberant projection develops in the hippocampus, and how the postsynaptic receptors respond to the increased input. Morphological analyses will be performed using fluorescence histochemical and immunocytochemical techniques and high affinity uptake of 3H norepinephrine, endogenous biogenic amine content, and B-adrenergic receptor binding for the biochemical analyses. In addition, by intraocular grafting methods, the abnormal growth will be assessed to determine whether this phenomenon is an intrinsic property of LC neurons in tg/tg or whether the target neurons in the hippocampus control the formation of the NE axonal arborization. The tottering genetic mutation is unique in that it provides both a model for examining basic developmental mechanisms that govern the formation of proper connectivity by CNS neurons and a means in the future for defining those factors that may lead to learning and memory dysfunctions as a consequence of the abnormal development of the LC neuron system.